Immune Combo Active in Relapsed/Refractory AML

Response, survival with nivolumab and azacitidine top historical data

Patients with relapsed/refractory acute myeloid leukemia (AML) responded better and lived longer than historical benchmarks when they received an immune checkpoint inhibitor in addition to standard therapy, a preliminary trial showed.

A third of the 70 patients enrolled in the study had objective responses to the combination of nivolumab (Opdivo) and azacitidine (Vidaza), including complete responses in 22%. More than half of patients with no prior exposure to azacitidine or similar drugs responded to the combination.

The patients had a median overall survival (OS) of 6.3 months. Patients who received the combination in first relapse had a median survival of 10.6 months, double the survival of similar patients treated with azacitidine alone, reported Naval Daver, MD, of the MD Anderson Cancer Center in Houston, and colleagues online in Cancer Discovery.

"[With traditional therapies for relapsed/refractory AML] we've seen response rates, across multiple phase III studies, in the range of 15%-25%," Daver told MedPage Today. "The key findings were in two subsets where we saw much more encouraging response rates and overall survival: Patients who had no prior hypomethylating agent (HMA) treatment ... and the early-salvage population."

"If these results hold true, this could be a very good treatment option for the early-salvage patients or those who have not received azacitidine," he added.

HMAs, such as azacitidine and decitabine, promote antitumor immune signaling but dampen antitumor immune response by increase expression of the immune checkpoint molecules PD-1 and PD-L1 in solid tumors and in myelodysplastic syndrome (MDS). Upregulation of immune checkpoint molecules may play a role in development of resistance to HMAs, Daver's group noted.

In preclinical models of AML, disease progression was associated with increased PD-1 expression, leading to decreased T cell-mediated antitumor activity, which was partly reversible by PD-1 blockade, the authors continued. Anti-PD-1 drugs have demonstrated little single-agent activity in relapsed AML, high-risk MDS, or other hematologic malignancies, aside from classical Hodgkin's lymphoma. In contrast, rationally designed combinations have demonstrated activity in several types of blood cancers.

Azacitidine has approval in the U.S. and Europe for treatment of MDS. Additionally, the drug has approval in Europe for older patients with newly diagnosed AML and is commonly used in that setting in the U.S. Collectively, available evidence suggested that adding an immune checkpoint inhibitor to azacitidine might improve anticancer activity in AML.

Daver and colleagues evaluated the combination of nivolumab and azacitidine in a phase II trial involving patients with relapsed/refractory AML, a median age of 70, and who had received a median of two prior therapies for AML. Treatment history included prior exposure to HMAs in 45 of the 70 patients. The primary objectives were the safety and efficacy of the combination.

The regimen led to objective responses in 23 of 70 patients (33%). The overall response rate comprised four complete responses, 11 complete responses with incomplete cell recovery, one partial response, and seven patients who had improvement in at least one hematologic parameter for >6 months. Six other patients had stable disease for >6 months. A subgroup of patients with no prior HMA treatment had an objective response rate of 58%.

For comparison, investigators referenced a historical control group of 172 patients with relapsed/refractory AML treated with HMAs, which resulted in an objective response rate of 20%. Patients with no prior exposure to HMAs did no better than the overall group. Those findings were consistent with a recent multicenter analysis of HMA therapy showing an overall response rate of 25% in 655 patients with relapsed/refractory AML and no previous treatment with HMAs.

Daver and colleagues reported that 57 of the 70 patients died during a median follow-up of 21.4 months. The median OS of 6.3 months was significantly better than the 4.6-month median for the historical control group (P=0.013). The subgroup of 25 patients who received the combination in first relapse had a median survival of 10.6-months, double the 5.3-month median for "first salvage" patients in the historical control group (P=0.011).

Pre-planned biomarker analyses showed that higher pretreatment levels of CD3 and CD8 cells in bone marrow predicted an increased likelihood of response, said Daver. CD3 cells had higher sensitivity and specificity for response, suggesting potential as a marker for selecting patients for treatment.

Grade 2 and grade 3/4 immune toxicities occurred in eight patients each, but 14 of the 16 patients responded to steroid therapy. The most common immune toxicities were pneumonitis (nine episodes), nephritis (six), skin rash (three), and liver enzyme elevation (two). Grade 3/4 immune-related toxicities led to treatment discontinuation in 13% of patients. Two patients died of treatment-refractory pneumonitis.

"There are unique immune toxicities that are not familiar to leukemia doctors, even in major centers. We want to stress the importance of awareness of these immune toxicities, monitor for them, and to treat them very quickly at the earliest suspicion with high-dose steroids," Daver stated.

The next step in evaluating immune therapy in AML will focus on other combinations, including three-drug combinations. Preliminary results from an ongoing trial that will be reported at the American Society of Hematology meeting in December showed a 43% response rate in patients who received nivolumab, azacitidine, and ipilimumab (Yervoy), another type of immune checkpoint inhibitor.

The study was supported by the National Cancer Institute and Bristol-Myers Squibb (BMS).

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